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Mitotoxicity in distal symmetrical sensory peripheral neuropathies

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From Nature Reviews Neurology

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A Correction to this article was published on 01 July 2014

This article has been updated

Key Points

  • Experiments in animal models of chronic distal symmetrical sensory peripheral neuropathies have demonstrated mitochondrial dysfunction in primary afferent sensory neurons

  • The mitochondrial dysfunction manifests as a cellular energy deficit, and has been linked to the emergence of spontaneous discharges and compartment-specific degeneration beginning with the terminal receptor arbor of the afferent neurons

  • Although the mitotoxic mechanisms differ according to aetiology, the consequences of the energy deficit are consistent and account for the similarity of symptoms across conditions

  • According to the mitotoxicity hypothesis, drugs that protect or restore mitochondrial function could aid the prevention and treatment of chronic distal symmetrical sensory peripheral neuropathies; preliminary data support this prediction

Abstract

Chronic distal symmetrical sensory peripheral neuropathy is a common neurological complication of cancer chemotherapy, HIV treatment and diabetes. Although aetiology-specific differences in presentation are evident, the clinical signs and symptoms of these neuropathies are clearly similar. Data from animal models of neuropathic pain suggest that the similarities have a common cause: mitochondrial dysfunction in primary afferent sensory neurons. Mitochondrial dysfunction is caused by mitotoxic effects of cancer chemotherapeutic drugs of several chemical classes, HIV-associated viral proteins, and nucleoside reverse transcriptase inhibitor treatment, as well as the (possibly both direct and indirect) effects of excess glucose. The mitochondrial injury results in a chronic neuronal energy deficit, which gives rise to spontaneous nerve impulses and a compartmental neuronal degeneration that is first apparent in the terminal receptor arbor—that is, intraepidermal nerve fibres—of cutaneous afferent neurons. Preliminary data suggest that drugs that prevent mitochondrial injury or improve mitochondrial function could be useful in the treatment of these conditions.

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Figure 1: Clinical symptoms and biomarkers of chronic distal symmetrical sensory peripheral neuropathy.
Figure 2: Underlying mechanisms in the development of distal symmetrical sensory peripheral neuropathy.
Figure 3: Contribution of nitro-oxidative stress to mitochondrial dysfunction.
Figure 4: Peroxynitrite decomposition catalysts.

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Change history

  • 01 July 2014

    In the version of this article initially published, 'nitric oxide' was referred to as 'nitrogen oxide', and the generation of peroxynitrite by superoxide ion-nitric oxide interaction was not clearly illustrated. Moreover, the fact that selective peroxynitrite decomposition catalysts act on peroxynitrite alone, whereas dual manganese superoxide dismutase mimetics and peroxynitrite decomposition catalysts eliminate both peroxynitrite and potentially beneficial superoxide ions, was not clearly indicated in Figure 4. These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We regret that space limitations prevented us from giving proper acknowledgement in the reference list of the many investigators who have contributed to this field. To compensate, we have attempted to cite recent articles that do reference their contributions.

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Authors and Affiliations

  1. Department of Anaesthesia, Faculty of Dentistry, and The Alan Edwards Centre for Research on Pain, McGill University, 3655 Promenade Sir William Osler, Montréal, H3G 1Y6, QC, Canada

    Gary J. Bennett

  2. Department of Pharmacological and Physiological Sciences, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St Louis, 63104, MO, USA

    Timothy Doyle & Daniela Salvemini

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All three authors provided substantial contributions to discussions of the content of the manuscript, researched the literature, and participated in writing, editing and revision of the manuscript.

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Correspondence to Gary J. Bennett.

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Competing interests

D.S. and the Saint Louis University School of Medicine have patents concerning the use of superoxide dismutase mimetics and peroxynitrite decomposition catalysts for the treatment and prevention of neuropathic pain (WO 2012033916 A1 20120315; US 20080318917 A1 20081225; WO 2005060437 A2 20050707; US 6214817 B1 20010410; WO 9858636 A1 19981230). G.J.B and T.D. declare no competing interests.

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Bennett, G., Doyle, T. & Salvemini, D. Mitotoxicity in distal symmetrical sensory peripheral neuropathies. Nat Rev Neurol 10, 326–336 (2014). https://doi.org/10.1038/nrneurol.2014.77

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